| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Physiological processes [G07] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
1.) Phase I: Safety determination of the treatment with SLAMF7 CAR-T;
2.) Phase I: Determination of the MTD and the recommended phase IIa dose of SLAMF7 CAR-T
3.) Phase IIa: Safety determination of the treatment with SLAMF7 CAR-T;
4.) Phase IIa: Evaluation of the efficacy, defined as overall response rate (ORR) of SLAMF7 CAR-T in patients with MM |
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| E.2.2 | Secondary objectives of the trial |
1.) Evaluation of the complete response (CR) of SLAMF7 CAR-T in patients with MM
2.) Determination of the feasibility to ex vivo manufacture of autologous SLAMF7 CAR-T and to administer to patients with MM;
3.) Determination of the expansion and duration of in vivo persistence of adoptively transferred SLAMF7 CAR- T cells in peripheral blood, bone marrow and tumor tissue;
4.) To determine if the adoptive transfer of SLAMF7 CAR-T has an anti-myeloma effect;
5.) Determination of the SLAMF7 CAR-T cells impact on patient’s overall survival (OS);
6.) To determine if the adoptive transfer of SLAMF7 CAR-T affects the quality of life
Further exploratory objectives, please refer to the exploratory end points listed below
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed informed consent form.
2. Patient is ≥18 years of age.
3. Patient is willing and able to adhere to the protocol requirements.
4. Patient with diagnosis of MM who has been treated with at least 2 prior lines of treatment, including at least one cycle of high-dose chemotherapy with autologous hematopoietic stem cell transplantation if the patient was eligible, and exposure to an immunomodulatory imide drug (e.g. lenalidomide and/or pomalidomide), a proteasome inhibitor, and an anti-CD38 antibody.
(Note: Induction therapy, up to 2 cycles of high-dose chemotherapy with autologous hematopoietic stem cell transplantation, and subsequent consolidation and/or maintenance therapy are considered one line of treatment).
5. At least one of the following subcriteria must be measured in the patient:
- Serum M-protein greater or equal to 0.5 g/dL
- Urine M-protein greater or equal to 200 mg/24 h
- Serum free light chain (FLC) assay: involved FLC level greater or equal to 10 mg/dL (100 mg/L) provided serum FLC ratio is abnormal
- A biopsy-proven evaluable plasmacytoma
- Bone marrow plasma cells >10% of total bone marrow cells (>30% if bone marrow plasma cells are the only marker of measurable disease)
6. Patients previously treated with an anti-SLAMF7 antibody are eligible.
7. Karnofsky performance status ≥60%. If patient has a Karnofsky performance status <60% (e.g. after a spinal cord injury) but is judged to be medically fit by the investigator, patient is eligible.
8. Female patients of childbearing potential must:
a) have a negative pregnancy test (blood) at screening.
b) either commit to true abstinence from heterosexual contact or agree to use, and be able to comply with, effective measures of contraception without interruption, from screening through 1 year following the IMP infusion. A highly effective method of contraception or birth control (failure rate less than 1% per year when used consistently and correctly) must be practiced. The patient should be informed of the potential risks associated with becoming pregnant while enrolled in this clinical trial. Reliable methods for this trial are: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, sexual abstinence or vasectomized sexual partner. Abstinence is only accepted as true abstinence: when this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence [e.g. calendar, ovulation, symptothermal, post-ovulation methods and withdrawal] are not acceptable methods of contraception.) Postmenopausal (no menses for at least 1 year without alternative medical cause) or surgically sterile female patients (tubal ligation, hysterectomy or bilateral oophorectomy) may be enrolled.
c) Agree to abstain from breast feeding during the study participation and for 1 year after the IMP infusion.
9. Male patients must practice true abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential for at least 1 year after IMP infusion, even if he has undergone a successful vasectomy.
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| E.4 | Principal exclusion criteria |
1. Patient has undergone a prior allogeneic stem cell transplant with either standard or reduced intensity conditioning ≤12 months prior to leukapheresis.
2. Patient has undergone a prior allogeneic stem cell transplant with either standard or reduced intensity conditioning >12 months, and suffers on chronic Graft-versus-Host Disease and/or is on systemic immune-suppressants.
3. Patient with diagnosis of MM
a. in first relapse following an autologous stem cell transplantation or
b. in second relapse that subsequently achieves a complete response
that is considered being a candidate for an allogeneic stem cell transplantation, unless the patient explicitly denies undergoing an allogeneic stem cell transplantation.
4. Patient has received anti-CD38 and/or anti-SLAMF7 antibodies ≤8 weeks prior to leukapheresis.
5. Ongoing treatment with systemic immune-suppressants (e.g. systemic cyclosporine or systemic steroids at any dose).
(Note: Physiologic steroid replacement therapy, topical immune-suppresants as e.g. cyclosporine/tacrolimus eye drops, and topical steroids are permitted.)
6. Echocardiogram with left ventricular ejection fraction <45%.
7. Inadequate renal function defined by creatinine clearance ≤45 mL/min using Cockcroft-Gault equation.
8. Inadequate hepatic function defined by aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >2.5 x upper limit of normal (ULN) and total bilirubin >1.5 x ULN (unless due to Gilbert’s syndrome and direct bilirubin is ≤1.5 x ULN; unless due to intrahepatic myeloma lesions as demonstrated by magnetic resonance imaging [MRI] or positron emission tomography [PET]/computed tomography [CT] not older than 4 weeks prior to screening).
9. International ratio (INR) or partial thromboplastin time (PTT) >1.5 x ULN, unless on a stable dose of anti-coagulant.
10. Evidence of human immunodeficiency virus (HIV) infection.
11. Seropositive for and with evidence of active viral infection with hepatitis B virus (HBV), excluding
- Patients who are hepatitis B surface antigen negative and HBV viral deoxyribonucleic acid (DNA) negative
- Patients who had hepatitis B but have received an antiviral treatment and show non-detectable viral DNA for 6 months
- Patients who are seropositive because of hepatitis B virus vaccine
- Patients with known HBV infection but undetectable HBV viral load and on anti-viral therapy to prevent HBV reactivation.
12. Seropositive for and with active viral infection with hepatitis C virus (HCV), excluding
- Patients who had hepatitis C but had received an antiviral treatment and show no detectable HCV viral ribonucleic acid (RNA) for 6 months.
13. Seropositive for syphilis on treponema pallidum hemagglutination test, excluding
- Patients with negative treponema pallidum antibody absorption test result
14. Patients with active infection (e.g. asymptomatic and symptomatic severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection) or other serious medical or psychiatric disorder on investigators decision.
15. Pregnant or lactating women.
16. Current or previous (within 30 days of enrollment) treatment with another IMP.
17. Known abuse of alcohol, drugs, or medicinal products.
18. Employees of the sponsor, or employees or relatives of the investigator. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1.) Phase I: Type, frequency, and severity of adverse events (AEs), including serious adverse events (SAEs), cytokine release syndrome (CRS), and neurotoxicity (i.e. immune effector cell-associated neurotoxicity syndrome [ICANS])
2.) Phase I: MTD of SLAMF7 CAR-T that can be administered in phase IIa will be assessed at the end of phase I
3.) Phase IIa: Type, frequency, and severity AEs, including SAEs, CRS, and neurotoxicity (i.e. ICANS)
4.) Phase IIa: Percentage of patients who achieved partial response (PR) or better using the IMWG Uniform Response Criteria for Multiple Myeloma at Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21 and 24 after SLAMF7 CAR-T infusion |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1.) D0, 4 hours after infusion, D1 to D28, W5, W6, W7, W8, W10, W12, M4 to M12, M15, M18, M24
2.) End of phase I
3.) D0, 4 hours after infusion, D1 to D28, W5, W6, W7, W8, W10, W12, M4 to M12, M15, M18, M24
4.) M1 to M6, M9, M12, M15, M18, M21, M24 |
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| E.5.2 | Secondary end point(s) |
1.) Phase IIa: Percentage of patients who achieved CR or better using the IMWG Uniform Response Criteria for Multiple Myeloma at Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21 and 24 after SLAMF7 CAR-T infusion
2.) Phase I and IIa: Percentage of myeloma patients enrolled into the trial who receive ex vivo expanded autologous SLAMF7 CAR-T within the 48h shelf-life of the product
3.) Phase I and IIa: Maximum peak in SLAMF7 CAR-T (Cmax), time to peak of SLAMF7 CAR-T (Tmax), area under the curve of CAR-T CD4+ and CD8+ cells (AUC), including maximum expansion and duration of persistence of SLAMF7 CAR-T cells at Baseline, Days 1, 3, 7, 10, 14, 21, 28, Week 6, 8, 12, Months 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 21, 24
4.) Phase I and IIa:
a) Time between first SLAMF7 CAR-T infusion and first documentation of response at Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24;
b) Time between first response and disease progression PD or death at Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24
c) Time between SLAMF7 CAR-T infusion and first documentation of PD or death at Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24
d) Phase I and IIa: Proportion of minimal residual disease (MRD) evaluable patients that are MRD negative (defined at a minimum of 1 in 105 nucleated cells) using flow cytometry at Months 1, 3, 6, 12, 24
5.) Phase I and IIa: Time between SLAMF7 CAR-T infusion and time of death at Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24
6.) Patient-reported outcomes as measured by EORTC-QLQ-C30/-MY20 at Screening, Baseline, Months 6, 12, 24
Exploratory end points:
1.) Immunophenotype of SLAMF7 CAR-T and endogenous immune cells in the peripheral blood and bone marrow at Baseline, Months 1, 3, 6, 12, 24
2.) Cytokine/chemokine levels in the blood at Baseline, Days 0 (prior and after IMP infusion), 1, 3, 7, 10, 14, 21, 28, Week 6, 8, 12, Months 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 21, 24
3.) Humoral or cellular immune response against the SLAMF7 CAR-T at Months 1, 3, 6, 12, 24
4.) Change from Baseline in immunophenotype, gene expression profile, and clonal composition at Months 1, 3, 6, 12, 24
5.) Expression of SLAMF7 on myeloma cells and endogenous immune cells after SLAMF7 CAR-T therapy at Months 1, 3, 6, 12, 24
6.) Kinetic and frequency of SLAMF7 CAR-T after activation of the EGFRt depletion marker in peripheral blood (on Days 0, 1, 3, 7, 10, 14, 21, 28 after administering the first dose of anti-EGFR antibody) and in bone marrow (on Day 28 after administering the first dose of anti-EGFRt antibody)
7.) Number of inpatient intensive care unit (ICU) days, inpatient non-ICU days, outpatient visits and concomitant medications at Months 6, 12, 24
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.) M1 to M6, M9, M12, M15, M18, M21, M24
2.) D0
3.) Baseline (BL) (D-8), D1, D3, D7, D10, D14, D21, D28, W6, W8, W12, M4 to M12, M15, M18, M21, M24
4.a) M1 to M6, M9, M12, M15, M18, M21, M24
4.b.) M1 to M6, M9, M12, M15, M18, M21, M24
4.c) M1 to M6, M9, M12, M15, M18, M21, M24
4.d.) M1, M3, M6, M12, M24
5.) M1 to M6, M9, M12, M15, M18, M21, M24
6.) M6, M12, M24
Exploratory:
1.) BL, M1, M3, M6, M12, M24
2.) BL, D0 (prior and after IMP infusion), D1, D3, D7, D10, D14, D21, D28, W6, W8, W12, M4 to M12, M15, M18, M21, M24
3.) M1, M3, M6, M12, M24
4.) M1, M3, M6, M12, M24
5.) M1, M3, M6, M12, M24
6.) Peripheral blood: D0, D1, D3, D7, D10, D14, D21, D28 after first dose of anti-EGFR AB; bone marrow: D28 after first dose of anti-EGFRt AB
7.) M6, M12, M24 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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